Derivatives of amidine, mixture of isomers, or individual isomers, and their salts, the pharmaceutical composition having an antagonistic action on leukotriene b4

 

(57) Abstract:

Derivatives of amidine formula I, where R1and R2identical or different, denote hydrogen, halogen, alkyl, phenyl, possibly substituted with halogen, alkyl, alkoxyl or acyl, OR5where R5- H, alkyl, phenyl, possibly substituted with halogen, alkyl, alkoxyl or acyl group SO2R6where R6- alkyl, phenyl, COR6or R1and R2together, means associated with the adjacent carbon atoms of the benzene ring group-CR8=CR9-CH=CH-, -CH=CR8-CR9=CH -, or-CR8= CH-CR9= CH-, where R8and R9denote H, OH, alkyl, alkoxy, acyl, or-O-CHR10-CH2-, where R10Is H, alkyl or-CO-CH2-CH2-O-; R3- Oh, H, alkyl, alkoxy or acyl, phenyl; R4- H or alkoxy; A is one of the groups X1-A-X2(a) or X2-A2-X3(b) where A1-C2-4-alkylen, CIS - or TRANS-CH2-CH=CH-CH2-,

-CH2-CC-CH2or

< / BR>
< / BR>
A2- C1-5-alkylene, X1- O, imino, sulfur, sulfinil, sulfonyl, carbonyl, methylene; X2is oxygen atom or sulfur, aminogroup or

< / BR>
X3- NH-CO, CO-NH or SO2NH; B is a group CH=CH or CH=N, a mixture of them and the enta, has an antagonistic action on leukotriene B4and can be used in particular for the treatment of asthma, ulcerative colitis.

2 S. and 9 C.p. f-crystals, 5 PL.

H

Description

The invention relates to new nitrogen-containing chemical compounds which possess valuable biological properties, in particular to new derivatives of amidine, which may constitute the active principle of the pharmaceutical composition having an antagonistic action on leukotriene4.

Known derivatives of amidine, which may constitute the active principle of the pharmaceutical composition having an antagonistic action on leukotriene4(see U.S. patent N 4902700, class A 61 K 31/425, 1990).

Object of the invention is the expansion of the range of the derivative of amidine having antagonistic action on leukotriene4.

This task is solved proposed derivatives amidine General formula

< / BR>
In which

R1and R2- same or different and mean hydrogen, halogen, alkyl with 1 to 12 carbon atoms, phenyl, unsubstituted or substituted atom halogen means a hydrogen atom, alkyl with 1 to 12 carbon atoms, phenyl, unsubstituted or substituted by halogen atom, alkyl or alkoxygroup with 1 to 4 carbon atoms or acyl with 2 to 5 carbon atoms, a group of SO2R6where R6means alkyl with 1 to 12 carbon atoms, phenyl, unsubstituted or substituted by halogen atom, alkyl or alkoxygroup with 1 to 4 carbon atoms or acyl with 2 to 5 carbon atoms, or the group COR6where R6have the above significance, or R1and R2together, means associated with the adjacent carbon atoms of the benzene ring, unsubstituted or substituted by alkyl with 1 to 4 carbon atoms group-CR8=CR9-CH=CH-, -CH=CR8-CR9=CH -, or-CR8= CH-CR9= CH-, where R8and R9the same or different and mean a hydrogen atom, hydroxyl, alkyl, alkoxygroup with 1 to 4 carbon atoms or acyl with 2 to 5 carbon atoms, -O-CHR10-CH2-, where R10means a hydrogen atom or alkyl with 1 to 4 carbon atoms, -CO-CH2-CH2-O-

R3is hydroxyl, hydrogen atom, alkyl with 1 to 12 carbon atoms, alkoxy or acyl with 1 to 12 carbon atoms, phenyl, unsubstituted or substituted by halogen atom, alkyl or alkoxygroup with 1 to 4 carbon atoms or ACI is SCP a) or (b)

X1- A1- X2a)

X2- A2- X3b)

where

A1- alkylene with 2 to 4 carbon atoms, CIS - or TRANS-CH2-CH=CH-CH2the group CH2-C C-CH2or a group of the formula

< / BR>
A2-alkylene with 1 to 5 carbon atoms;

X1is an oxygen atom, aminogroup, a sulfur atom, sulfinil, sulfonyl, carbonyl, methylene;

X2is oxygen atom or sulfur, imino group or a group of the formula

< / BR>
X3is a group of formula NH-CO, CO-NH or SO2NH;

In group CH=CH or CH=N,

the mixture of isomers or individual isomers and their salts.

In the first group are preferably derivatives of amidine includes compounds of the above formula (I) in which R1and R2- same or different and mean a hydrogen atom, alkyl with 1 to 12 carbon atoms, acyl, or alkoxy with 1 to 12 carbon atoms, a halogen atom, or together, means associated with the adjacent carbon atoms of the benzene ring group-CR8=CR9-CH=CH-, -CH= CR8-CR9= CH-, -O-CHR10-CH2- or-CO-CH2-CH2-O, where R8, R9and R10have the above values,

R3is a hydrogen atom, alkyl with 1 to 12 carbon atoms, hydroxyl, alkoxy or acyl of 1 to 12 atoms in the above values, X2linked in the para-position relative to amidino group.

The second group preferred derivatives of amidine includes compounds of the above formula (I) in which R1, R2and R3mean acyl with 2 to 5 carbon atoms, a hydrogen atom; alkyl with 1 to 4 carbon atoms, hydroxyl and a hydrogen atom; an acyl with 2 to 5 carbon atoms, alkyl with 1 to 4 carbon atoms and a hydrogen atom; an acyl with 2 to 5 carbon atoms, hydroxyl and alkyl with 1 to 4 carbon atoms; hydroxyl, acyl with 2 to 5 carbon atoms and the alkyl with 1 to 4 carbon atoms.

In a third preferred group of derivatives of amidine includes compounds of the above formula (I) in which A denotes the group O-(CH2)2-O, O-(CH2)4-O or

< / BR>
In a fourth preferred group of derivatives of amidine includes compounds of the above formula (I), in which a group of the formula

< / BR>
means acetylphenyl.

In the fifth group of preferred derivatives of amidine includes compounds of the above formula (I) in which R4means a hydrogen atom, and B is the group CH= CH, with the remainder in A second ring connected in the para-position, relative to amidino group.

In a sixth group of preferred Ave is BR>< / BR>
in which

a = 0 or 1;

b = 1 or 2;

R is alkyl of I to 4 carbon atoms, or a hydrogen atom in the case when a = 0 or 1 and b = 1 if a = 1 and b = 2,

in the form of free base or acid salt additive.

In the seventh group of preferred derivatives of amidine includes compounds of the above formula (I) representing the compound of formula

< / BR>
in which

a = 0 or 1 and b = 1 or a = 0 and b = 2;

R is a hydrogen atom, methyl or ethyl.

Derivatives of amidino the above General formula (I) can be obtained with known methods, for example by

a) interaction of the compounds of General formula (II)

< / BR>
in which

R1- R4A and B have the above meanings, with R preferably denotes alkyl with 1 to 6 carbon atoms or benzyl (although a specialist may use derivatives other alcohols)

with ammonia, or

b) interaction of the compounds of General formula (III)

< / BR>
in which

Z means a group HE or SH a R1R2and R3have the above values,

with a compound of General formula (IV)

< / BR>
in which

B and R4have the above values, a Y connection means UB> X2and X3have the above meaning,

or in the interaction between the compounds of General formula (V)

< / BR>
in which

B, R4and Z have the above values,

with a compound of General formula (VI)

< / BR>
in which

R1, R2and R3have the above values, and W denotes a group of formula-X1-A1-L, X4-A2-L, -(CH2)1-2-NH-CO-(CH2)1-3-Z or-CH=CH-A2-L, where X1X4, A1, A2and L have the above values,

or d) recovery of the compounds of General formula (II)

< / BR>
in which

A, B, and R1- R4have the above values.

The interaction according to the above method (a) it is advisable carried out in a medium of an organic solvent at a temperature of from about 0oC to the boiling temperature of the reaction mixture, preferably from room temperature to about 100oC, or at the boiling point, if it is below the 100oC. Suitable solvents are polar solvents such as methanol, ethanol and propanol.

In the case of sufficiently acid starting compounds, the interaction can be done Interaction according to methods b) and C) is carried out in the environment aprotic solvent, such as dimethyl sulfoxide, dimethylformamide, acetonitrile, or an alcohol, such as methanol, ethanol or propanol, with the addition of the base (carbonate, hydroxide and metal hydride) at a temperature of from 0 to 140oC or at the boiling temperature of the reaction mixture.

Phenols or thiophenol can also be used in the form of salts, for example salts of alkali metals. As nucleofuge tsepliaeva group may contain halogen atoms such as bromine atom or chlorine.

As a result of interaction according to methods b) and C) get the derivative of amidine General formula (I) in which A is a group via an oxygen atom or sulfur linked to at least one of the ring systems.

Recovery according to method g) carry out catalytic hydrogenation, in particular, in the presence of Raney Nickel in a lower alcohol, for example methanol.

It is advisable amidoxime formula (VII) is dissolved in methanol with the addition of the calculated amount of acid salt which wish to obtain the target product, and hydronaut at room temperature and slightly elevated pressure, for example 5 bar, to the cessation of hydrogen absorption.

oC, preferably at room temperature.

The initial compounds of General formula (VII) can be obtained from the corresponding NITRILES, which are subjected to interaction with hydroxylamine.

The proposed connection can be used for the treatment of diseases, in particular, due to their antagonistic against leukotriene B4activity. Therefore they can be used, in particular, for the treatment of diseases, gastropathy, induced nestrogannye anti-inflammatory drugs. The new compounds can also be used in combination with other active substances, such as anti-allergic substances that promote the secretion of substances,2-adrenergicheskimi substances, steroids taken by inhalation, anti-histamine agents and/or antagonists of platelet-activating factor. The cottage can be done locally, through the mouth, through the skin, through the nose, intraperitoneally, or by inhalation.

Used for the treatment or prevention of a disease, the dose depends on the strength of individual compounds from the weight of the patient, as well as the type and severity of the disease. When the country through the mouth of the individual dose is from 10 to 250 mg, preferably from 20 to 200 mg, and in the country by inhalation, from about 2 to 20 mg of active substance. New connections can be given in the form of conventional drugs, such as tablets, pills, capsules, wafers, powders, granulates, solutions, emulsions, syrups, aerosols for inhalation, ointments, suppositories.

Therefore, another object of the invention is a pharmaceutical composition with antagonistic against leukotriene B4activity what Nisha least one compound of the above General formula (I) in an effective amount.

The following examples serve to illustrate the formulations of the compositions.

1. Tablets

Composition:

The proposed active substance - 20 weight.parts

Stearic acid - 6 weight.parts

Grape sugar - 474 weight.parts

All of these components in a known manner produce tablets weighing 500 mg. If necessary, you can increase or decrease the active substance and accordingly to increase or decrease the amount of grape sugar.

2. Suppositories

Composition:

The proposed active substance - 100 weight.parts

Lactose powder - 45 weight.parts

Cocoa butter - 1555 weight.parts

All of these components in a known manner produce suppositories weight of 1.7 g

3. Powder for inhalation

5 mg of powder of the active substance (particle size of approximately 0.5 to 7 μm) filled in capsules of hard gelatin, if necessary adding crushed to particles of lactose. The powder is inhaled using a known inhalation devices.

Activity of derivatives of amidine above formula (I) was investigated in the following experiments.

a) Experience associate leukotriene BPodavaemogo doses inhibit the binding of 3 nm3H-leukotriene B4live U937 cells (differentiated human monolta cell line with eksponirovanie naturally receptor leukotriene B4) (incubation at a temperature of 0oC for 2 hours). After separation of unbound3H-leukotriene B4by membrane filtration, the radioactivity of the complex receptor leukotriene B4and the associated3H-leukotriene B4determined by scintillation scanning. The binding constant of the inhibition of Ki) is determined by an iterative negotiation displacement curve to the measured values (the program: "the Interdependent balance of mass, using the computer Wang).

b) Aggregation of neutrophils Guinea pig

The induction of in vitro using leukotriene B4(the increase in light transmission in the apparatus for measuring the aggregation recorded in mm, dual definition in each experiment). Results: inhibition after 2 minutes after incubation with the test compound in the environment politial and dimethyl sulfoxide.

C) Induced leukotriene B4accumulation of neutrophils in the ear of a mouse

Evaluation of the accumulation of neutrophile is h per minute (see Bradley and others: J. Invest. Dermatol. N 78, page 206, 1982). Improving upon expiration of 6 hours after treatment of the left ear leukotriene B4(on both sides by 250 ng) compared to the right ear (25 μl of acetone as solvent).

Cottage connection through the mouth in 1% tylose 300 for 30 minutes before treatment with leukotriene B4. The results of the experiments see following formulas.

Binding3H-leukotriene B4with receptors in the spleen cells of the Guinea pig in the presence of 10% serum gives data on Kipartly significantly less than 1 μm, in particular from 0.2 to 0.02 mm. The inhibition induced leukotriene4aggregation of neutrophils is about 0.5 to 0.05 μm (value EC50).

Especially should be mentioned in this connection, the compounds obtained according to examples 1 and 5, as well as connections NN 9, 1, 12, 17, 18, 20, 21 according to the following table I, N 3 according to table II and N 2 according to table III.

The following examples illustrate how to obtain the proposed connections.

Example 1.

< / BR>
To a solution of 2.0 g of 7-{4-(4-cyano-phenoxy)-E-bottles(2)-enyloxy]-8 - propyl-4H-1-benzo-Piran-4-it in 50 ml of chloroform and 1.5 ml of ethanol is added 5 ml of a solution of chloride of carbon in 17% of ordinary diet the Ute simple diethyl ether. The result of 1.15 g of the hydrochloride of 7-[4-(4-imido - carboxyethyl-phenoxy)-E-bug(2)-enyloxy] -8-propyl-4H-1-benzopyran-4 - it. Complex amidoamine add 50 ml of ethanolic ammonia solution (5M) and heated at a temperature of 70oC for 3 hours. The resulting mixture was evaporated, and the residue is subjected to chromatography on silica gel using as eluent a mixture of chloroform and methanol in the ratio of 7 : 3. As a result of recrystallization from a mixture of dichloromethane and simple diethyl ether to obtain 0.6 g of the hydrochloride of 7-[4-(4-amidino-phenoxy)-E-bottles(2)-enyloxy] -8-propyl-4H-1-benzopyran - 4-it; melting point: 144 - 148oC.

Example 2.

In a solution of 2.5 g of 4-[4-(2-propyl-3-methoxy-phenoxy)- butyloxycarbonyl obtained from 2-propyl-3-methoxy-phenol and 4 - bromooxindole in 40 ml ethanol at -20oC with stirring for one hour introducing hydrogen chloride. The resulting mixture was allowed to stand at room temperature for 16 hours. The solvent is then evaporated in vacuo, and the residue is absorbed in 50 ml of ethanol. Drops add a mixture of 14 ml of ethanolic ammonia solution and 50 ml of ethanol. The resulting mixture was allowed to stand at room temperature for 24 hours. Rast is enta mixture of chloroform and methanol in the ratio 8 : 2. The result is 1.8 g of the hydrochloride hemihydrate 4-[4-(2-propyl-3-methoxy-phenoxy)-Butylochka] - benzamidine; melting point: 117 -121oC.

Example 3.

< / BR>
In a solution of 32.0 g of 4-[(4-acetyl-2-isopropyl-5-methyl-phenoxy)- Butylochka] -benzonitrile in 350 ml of ethanol at -20oC enter of hydrogen chloride and optionally stirred for 48 hours. The formed crystals are sucked off and washed with simple diethyl ether. The result of 41.0 g of the hydrochloride of complex 4-[4-(4-acetyl-2-isopropyl-5-methyl-phenoxy)-Butylochka] - benzamido-ethyl ester (melting point: 100 - 102oC, decomposition). 15.0 g of This complex amidoamine at room temperature in several portions added to 33 ml of ethanolic ammonia solution (5M) and 100 ml of ethanol. The resulting mixture was stirred at room temperature for 36 hours, the mixture is evaporated, and the residue is stirred with 50 ml of water. The residue is sucked off, recrystallized from 30 ml of ethanol, and optionally washed with a simple diethyl ether. Gain of 11.5 g of the hydrochloride of 4-[4-(4 - acetyl-2-isopropyl-5-methyl-phenoxy)-Butylochka] -benzamidine; melting point: 182 - 183oC (decomposition).

Example 4.

< / BR>
Into a solution of 3.0 g of 4-[4-(4-cyano-Fe is W ill result of hydrogen chloride. The resulting mixture was allowed to stand at room temperature for 16 hours. The solvent is evaporated in vacuo, and the residue is absorbed in 50 ml of ethanol. Drops add a mixture of 14 ml of ethanolic ammonia solution and 50 ml of ethanol, and the resulting mixture allowed to stand at room temperature for 24 hours. The solvent is evaporated, and the residue is subjected to chromatography on silica gel grade 60 using as eluent a mixture of chloroform and methanol in the ratio of 7 : 3, resulting in a gain of 0.3 g of 4-[4-(4-amidino-phenoxy)butylamino]-acetophenone; melting point: 200 - 202oC.

Example 5.

< / BR>
of 8.2 g of 4-acetyl-3-methoxy-2-propyl-phenol are dissolved in 80 ml of dimethylformamide, and the resulting solution was added in several portions 1.1 g of sodium hydride as an 80% dispersion in vaseline oil. The resulting mixture is heated at a temperature of 80oC for 30 minutes and add a solution of 5.75 g of 4-(4-brometalia)-benzamidine obtained from dibromobutane and 4-cyanobenzoyl 4-(4-brometalia)-benzonitrile, in 40 ml of dimethylformamide. After 5 hours at 80oC is allowed to cool, acidified with ethereal hydrochloric acid, and the solvent is distilled off in vacuum. The residue is absorbed in ethanol and Phi is eshivot with simple diethyl ether. In the result of desantirovaniya get the 5.65 g of yellow-brown oil, which was subjected to chromatography on silica gel using as eluent a mixture of chloroform and methanol in the ratio of 7 : 3. The result is 2.4 g of oil which crystallized from toluene. The obtained product is dissolved in acetonitrile and acidified with ethereal hydrochloric acid. The crystals are sucked off, washed with cold acetonitrile, dissolved in water and after adding 2n. hydrochloric acid is re-crystallized. Obtain 0.8 g of the hydrochloride of 4- [4-(4-acetyl-3-methoxy-3-propylenoxide)-butylthio]-benzamidine; melting point: 120 - 122oC.

Example 6.

a) 4-[4-acetylphenol)-butoxy]-benzamidoxime.

In 300 ml of dimethylformamide is dissolved 45.6 g (0.3 mol) of 4 - oxybenzaldehyde and 81.3 g (0.3 mol) of 4-bromo-butoxy-acetophenone. Add to 55.2 g (0.4 mol) of anhydrous potassium carbonate and heated at a temperature of 80oC for 2 hours. Inorganic salts are sucked off, concentrated in vacuo and recrystallized from acetonitrile. Output: 47,8, melting Point: 164,5 - 165,5oC.

a) 3-[4-(4-acetylphenol)butoxy]-benzamidine-methanesulfonate.

of 47.8 g of compound obtained in stage a), is dissolved V Raney, then subjected to hydrogenation at a pressure of 5 bar to stop water absorption. Sucked off, the solvent evaporated in vacuum and recrystallized from ethanol.

Output: 45,2,

Melting point: 204 - 204,5oC.

According to the above methods you can obtain further compounds of General formula (I). In the following tables, "Ac" means the group of CH3CO.

1. Derivatives of amidine General formula I

< / BR>
where R1and R2- same or different and represent hydrogen, halogen, alkyl with 1 to 12 carbon atoms, phenyl, unsubstituted or substituted by halogen atom, alkyl or alkoxygroup with 1 to 4 carbon atoms or acyl with 2 to 5 carbon atoms, group OR5where R5means a hydrogen atom, alkyl with 1 to 12 carbon atoms, phenyl, unsubstituted or substituted by halogen atom, alkyl or alkoxygroup with 1 to 4 carbon atoms or acyl with 2 to 5 carbon atoms, a group of SO2R6where R6means alkyl with 1 to 12 carbon atoms, phenyl, unsubstituted or substituted by halogen atom, alkyl or alkoxygroup with 1 to 4 carbon atoms or acyl with 2 to 5 carbon atoms, or the group COR6where R6have the above significance, or R is whether substituted by alkyl with 1 to 4 carbon atoms group, -CR8= CR9- CH = CH-, -CH = CR8- CR9= CH -, or-CR8= CH - CR9= CH-, where R8and R9the same or different and mean a hydrogen atom, hydroxyl, alkyl, alkoxygroup with 1 to 4 carbon atoms or acyl with 2 to 5 carbon atoms, -O-CH R10- CH2-, where R10means a hydrogen atom or alkyl with 1 to 4 carbon atoms, -CO - CH2-CH2-O - ;

R3is hydroxyl, hydrogen atom, alkyl with 1 to 12 carbon atoms, alkoxy or acyl with 1 to 12 carbon atoms, phenyl, unsubstituted or substituted by halogen atom, alkyl or alkoxygroup with 1 to 4 carbon atoms or acyl with 2 to 5 carbon atoms, and R3means a hydrogen atom in the case when at least one of the substituents R1and R2does not mean a hydrogen atom;

R4is a hydrogen atom or alkoxy with 1 to 4 carbon atoms,

A - one of the groups a) or b):

X1- A1- X2a)

X2- A2- X3b)

where A1- alkylene with 2 to 4 carbon atoms, CIS - or TRANS - CH2- CH = CH - CH2the group CH2- C C - CH2or a group of the formula

< / BR>
A2- alkylene with 1 to 5 carbon atoms;

X1is an oxygen atom, aminogroup, a sulfur atom, sulfinil, su is>X3is a group of formula NH-CO, CO - NH or SO2NH;

B - group CH = CH or CH = N,

the mixture of isomers or individual isomers and their salts.

2. Derivatives of amidine formula I under item 1, in which R1and R2the same or different and mean a hydrogen atom, alkyl with 1 to 12 carbon atoms, acyl, or alkoxy with 1 to 12 carbon atoms, a halogen atom or together, means associated with the adjacent carbon atoms of the benzene ring group CR8= CR9- CH = CH-, -CH = CR8- CR9= CH-, -O-CHR10- CH2- or-CO - CH2-CH2-O, where R8, R9and R10have the above meanings; R3is a hydrogen atom, alkyl with 1 to 12 carbon atoms, hydroxyl, alkoxy or acyl with 1 to 12 carbon atoms; B is a group CH = CH; A is a group - X1- A1- X2- where X1X2and A1have the above meanings and X2linked in the para-position relative to amidinopropane.

3. Derivatives of amidine formula I under item 1, in which R1, R2and R3mean acyl with 2 to 5 carbon atoms, a hydrogen atom, alkyl with 1 to 4 carbon atoms, hydroxyl and a hydrogen atom; an acyl with 2 to 5 carbon atoms, alkyl with 1 to 4 carbon atoms and a hydrogen atom; an acyl with 2 to 5 carbon atoms, hydroxyl and aprosodia of amidine formula I on p. 1, in which A denotes the group O - /CH2/2- O O - /CH2/4- O or

< / BR>
5. Derivatives of amidine formula I under item 1 and 2, in which the group

< / BR>
means acetylphenyl.

6. Derivatives of amidine formula I on p. 1, 3, 4 or 5, in which R4means a hydrogen atom, and B is the group CH = CH, with the remainder in A second ring connected in the para-position relative to amidinopropane.

7. Derivatives of amidine formula I on p. 1, representing a compound of formula

< / BR>
in which a = 0 or 1;

b = 1 or 2;

R is alkyl with 1 to 4 carbon atoms or a hydrogen atom in the case when a = 0 or 1 and b = 1 if a = 1 and b = 2,

in the form of free base or acid salt additive.

8. Derivatives of amidine under item 7, in which a = 0 or 1 and b = 1 or a = 0 and b = 2, in the form of free base or acid salt additive.

9. Derivatives of amidine under item 8, in which R is a hydrogen atom, methyl or ethyl, a = 0 or 1, b = 1, in the form of free base or acid salt additive.

10. Derivatives of amidine under item 8, in which a = 0, b = 2 and R is methyl, in the form of free base or acid salt additive.

11. Pharmaceutical composition having an antagonistic action is characterized in that as active principle it contains an effective amount of a derivative of amidine formula I, as described in paragraph 1, the mixture of its isomers or isomer, or a pharmaceutically acceptable salt.

Priority signs and items:

05.02.92 - all values radicals p. 1, except for the value of the radical X2concerning the group of the formula

< / BR>
and PP.2 to 6 and 11.

24.12.92 - value of the radical X2concerning the group of the formula

< / BR>
and PP.7 - 10.

14.01.93 - according to the filing date of international application PCT/EP 93/00070 the value of the radicals R1and R2related groups - CR8= CR9- CH = CH-, -CH = CR8- CR9= CH and CR8= CH - CR9= CH in which R9means alkoxy with 1 to 4 carbon atoms.

 

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< / BR>
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